MS4A1

Official Full Name

membrane spanning 4-domains A1

Organism

Homo sapiens

GeneID

931

Background

This gene encodes a member of the membrane-spanning 4A gene family. Members of this nascent protein family are characterized by common structural features and similar intron/exon splice boundaries and display unique expression patterns among hematopoietic cells and nonlymphoid tissues. This gene encodes a B-lymphocyte surface molecule which plays a role in the development and differentiation of B-cells into plasma cells. This family member is localized to 11q12, among a cluster of family members. Alternative splicing of this gene results in two transcript variants which encode the same protein. [provided by RefSeq, Jul 2008]

Synonyms

B1; S7; Bp35; CD20; FMC7; CVID5; LEU-16;

Bio Chemical Class

CD20 calcium channel

Protein Sequence

MTTPRNSVNGTFPAEPMKGPIAMQSGPKPLFRRMSSLVGPTQSFFMRESKTLGAVQIMNGLFHIALGGLLMIPAGIYAPICVTVWYPLWGGIMYIISGSLLAATEKNSRKCLVKGKMIMNSLSLFAAISGMILSIMDILNIKISHFLKMESLNFIRAHTPYINIYNCEPANPSEKNSPSTQYCYSIQSLFLGILSVMLIFAFFQELVIAGIVENEWKRTCSRPKSNIVLLSAEEKKEQTIEIKEEVVGLTETSSQPKNEEDIEIIPIQEEEEEETETNFPEPPQDQESSPIENDSSP

Open

Disease

Acute myeloid leukaemia, Bacterial infection, B-cell lymphoma, Diabetes mellitus, Diffuse large B-cell lymphoma, Follicular lymphoma, Leukaemia, Lupus erythematosus, Lymphoma, Malignant haematopoietic neoplasm, Mature B-cell leukaemia, Mature B-cell lymphoma, Multiple sclerosis, Pancreatic cancer, Pemphigus, Rheumatoid arthritis, Solid tumour/cancer, Supraventricular tachyarrhythmia, Tension-type headache, Thrombocytopenia

Approved Drug

12 +

Clinical Trial Drug

46 +

Discontinued Drug

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Detailed Information

MS4A1, designated as Membrane Spanning 4-Domains A1, is located on the long arm of chromosome 11 (11q12.2) and encodes a protein more commonly known as CD20. This gene belongs to the larger MS4A gene family, characterized by members containing four transmembrane domains, intracellular N- and C-termini, and a conserved structural motif. The CD20 protein is a non-glycosylated phosphoprotein expressed almost exclusively on the surface of B lymphocytes, spanning from pre-B cells through mature B cells, with expression diminishing upon terminal differentiation into plasma cells. Its expression pattern renders it a quintessential lineage marker for B cells in both physiological and pathological contexts.

The MS4A1 gene produces a protein that forms homo-oligomers, likely tetramers, within the plasma membrane, creating functional calcium ion (Ca²⁺) channels. The protein's structure includes two extracellular loops, with the larger loop between transmembrane domains 3 and 4 being critical for antibody recognition. An important paralog, MS4A8, shares structural homology but exhibits distinct expression patterns and functions. Gene Ontology annotations highlight its critical functions, including potential roles in epidermal growth factor receptor binding and MHC class II protein complex binding, although the latter's precise functional significance requires further elucidation. Its involvement in pathways like "11p11.2 copy number variation syndrome" and "Extrafollicular and follicular B cell activation by SARS-CoV-2" underscores its relevance in immune responses and genomic disorders.

Biological Significance and Functional Mechanisms

CD20 plays a fundamental and non-redundant role in B-cell physiology, primarily functioning as a component of a store-operated calcium (SOC) channel complex. Upon engagement of the B-cell receptor (BCR) by antigen, CD20 facilitates the sustained influx of extracellular calcium ions (Ca²⁺) necessary for the robust intracellular signaling cascades that drive B-cell activation, proliferation, differentiation, and survival. This calcium influx occurs after the initial release of calcium from intracellular endoplasmic reticulum stores mediated by the BCR signalosome.

Figure 1. A schematic view of interacting partners of CD20 on the cell membrane and mechanisms of CD20 gene (MS4A1) regulation in malignant B cells. (Pavlasova G, et al., 2020)

The precise molecular mechanism involves CD20 oligomers forming or regulating calcium-conducting pores in the plasma membrane, allowing Ca²⁺ entry. This is critical for activating transcription factors like NFAT (Nuclear Factor of Activated T-cells), which orchestrate the expression of genes essential for effective humoral immune responses. The absence of CD20 expression on hematopoietic stem cells and plasma cells makes it an ideal therapeutic target, as its modulation selectively impacts the mature B-cell compartment without ablating the stem cell reservoir or eliminating antibody-producing plasma cells immediately.

While CD20 itself lacks intrinsic kinase activity or direct signaling motifs, its function as a calcium channel modulator positions it as a crucial amplifier of BCR signaling intensity and duration. This mechanism fine-tunes B-cell fate decisions in response to antigenic stimulation within secondary lymphoid organs. Its involvement in viral infection pathways, such as SARS-CoV-2, further highlights its role in shaping both extrafollicular (rapid, short-lived) and germinal center (high-affinity, long-lived) B cell responses.

Clinical Relevance and Therapeutic Applications

The clinical significance of MS4A1/CD20 is immense, spanning immunodeficiency disorders, autoimmune diseases, and hematological malignancies. Germline mutations in MS4A1 are associated with Common Variable Immunodeficiency 5 (CVID5), a primary immunodeficiency characterized by hypogammaglobulinemia, impaired specific antibody production, and recurrent infections. This underscores the gene's non-redundant role in normal human B-cell function and antibody responses.

Beyond genetic deficiencies, CD20 is the target of revolutionary immunotherapeutic monoclonal antibodies (mAbs) that have transformed the treatment landscape for B-cell malignancies and autoimmune conditions. Rituximab, the first approved anti-CD20 mAb, demonstrated unprecedented efficacy in non-Hodgkin lymphomas (NHL), particularly diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), leading to its widespread adoption and establishing CD20 as a validated target in oncology.

The mechanism of action of anti-CD20 antibodies involves multiple potential effects: direct induction of apoptosis upon binding, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC) mediated by Fc-receptor-bearing immune effector cells like natural killer cells and macrophages. Subsequent generations of anti-CD20 antibodies, such as ofatumumab (binding a distinct epitope with enhanced CDC), obinutuzumab (glycoengineered for enhanced ADCC and direct cell death), and ublituximab, have been developed to improve efficacy, overcome resistance, or offer subcutaneous administration.

In autoimmune diseases, particularly rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS), B-cell depletion therapies targeting CD20 have proven highly effective. These therapies demonstrate that B cells play critical roles beyond antibody production, including antigen presentation, T-cell modulation, and cytokine production, in driving autoimmune pathology. The profound and often prolonged B-cell depletion achieved by these therapies necessitates careful management of associated risks, including increased susceptibility to certain infections (e.g., reactivation of hepatitis B, progressive multifocal leukoencephalopathy by JC virus) and potential hypogammaglobulinemia with long-term use.

Ongoing research explores novel CD20-targeted modalities like bispecific antibodies (e.g., mosunetuzumab, glofitamab) and chimeric antigen receptor T-cell (CAR-T) therapies, further cementing CD20's position as a cornerstone of modern immunotherapy. The investigation into CD20's role in SARS-CoV-2 B-cell activation pathways also opens avenues for understanding immune responses to novel pathogens and potential therapeutic interventions.

Thus, MS4A1/CD20 stands as a paradigm of how understanding fundamental B-cell biology can lead to transformative clinical therapies across diverse disease states.

References:

Pavlasova G, Mraz M. The regulation and function of CD20: an "enigma" of B-cell biology and targeted therapy. Haematologica. 2020 Jun;105(6):1494-1506.
Mattiola I, Mantovani A, Locati M. The tetraspan MS4A family in homeostasis, immunity, and disease. Trends Immunol. 2021 Sep;42(9):764-781.

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